There is a clear, but poorly understood, link between estrogen and the autoimmune disease systemic lupus erythematosis (SLE). Humans are commonly exposed to Bisphenol A (BPA), a component of epoxy resins and plastics such as polycarbonate, and BPA binds to estrogen receptors to induce physiological changes. SLE-prone NZB/WF1 mice fed a small dose of BPA comparable to that obtained after a single application of an epoxy dental sealant, show a delay of onset of SLE symptoms and altered cytokine profiles. SLE symptoms arise from tissue damage caused by autoantibody production. Antigen presenting cells (APCs) are necessary for the activation of CD4+ T cells, whose help is required for autoreactive B cell differentiation and subsequent autoreactive antibody production. Given the requirement for MHC-II antigen presentation by APCs in this system and the core role that lysosomal proteases, cathepsins, play in this process, we will investigate the regulation of cathepsins by estrogen and bisphenol A in normal (BALB/c and C57BL/6J) and SLE-prone (NZB/WF1) mice. Using Western blots and active-site directed biotinylated probes, we will establish if there are cathepsin expression or activity variations in APCs (B cells, dendritic cells, and macrophages) between normal and SLE-prone mice as well as between healthy mice and those with the disease. In addition, we will establish if cathepsins are regulated by estrogen and BPA through ex vivo exposure of APCs, and if the regulation varies between normal and SLE-prone mice. Moreover, in vivo regulation by BPA will be monitored in mice fed physiologically relevant levels of the compound. These investigations will provide basic information on the interplay between the endocrine and immune systems and the specific effect of this interplay on the autoimmune disease SLE. It will also clarify the role of the endocrine disrupting chemical BPA on a central class of enzymes. [unreadable] [unreadable]